JC virus (JCV) is a polyomavirus which infects 86% of the general population. Asymptomatic primary infection occurs in childhood, and the virus remains quiescent in healthy individuals. In the context of immunosuppression, JCV can reactivate, causing a demyelinaing diseae of the brain called progressive multifocal leukoencephalopathy (PML). There is no cure for this disease, which classically occurs in patients with hematologic malignancies, solid organ and bone marrow transplants, and HIV/AIDS. Our preliminary studies have established bone marrow as a reservoir of JCV, but the course of primary infection, the nature of JCV latency in infected cells and the mechanisms that lead to JCV transformation and reactivation in the host have not been investigated. Furthermore, HIV infection is the largest risk factor for development of PML where, in contradistinction to healthy individuals, JCV is detected in the blood of 20% of HIV positive patients. Therefore, we hypothesize that a) primary Infection of JCV establishes viral latency In the kidney and the hematopoietic organs, b) the co-presence of HIV In the hematopoietic system Induces JCV neurotropic transformation, and c) reactivation of JCV is modulated by the cellular immune response. To test these hypotheses, we propose to: 1. Analyze JCV and HIV interactions in the hematopoietic system in histological samples and a cell culture model 2. Establish JCV Infection In the humanized mouse model and characterize factors that influence JCV reactivation after HIV co-infection 3. Decipher the impact of the cellular Immune response on JCV In Individuals undergoing allogeneic hematopoietic stem cell transplantation Dr. Tan's development as an independent investigator will be at the Beth Israel Deaconess Medical Center, guided by her mentor Dr. Igor Koralnik, Associate Professor of Neurology, Harvard Medical School. A committee of distinguished scientists will oversee her progress towards independence. Dr. Tan is committed to pursuing a career as an academic Investigator in the field of Neurovirology and Immunodeficiency. PUBLIC HEALTH RELEVANCE: JC virus causes progressive multifocal leukoencephalopathy (PML) In Immunocompromised Individuals, especially those with HIV Infection. The reservoir of JC virus is not known, but evidence points to the bone marrow. We propose to study JC virus reactivation and transformation in bone marrow of HIV positive and HIV negative patients. These studies may contribute to finding a cure for this deadly disease.